WD repeat-containing protein 72 (WDR72) has been localized in enamel organ, kidney and brain although its physiological function is not known. Mutations in the human WDR72 gene result in amelogenesis imperfecta. The affected enamel is poorly mineralized, indicating a potential role of WDR72 at the maturation stage of enamel formation. Our preliminary structure predictions suggest that WDR72 functions as a vesicle coatomer, like its homolog WDR7, playing a role in vesicle trafficking. To investigate the potential role of WDR 72 in vesicle trafficking in ameloblasts, we will use the homozygous mouse line with a Wdr72 null allele, which we generated from the NIH funded Knockout Mouse Project (KOMP), since our previous submission. We will determine whether WDR72 co-localizes with intracellular vesicles of ameloblasts. The role of WDR72 in the enamel matrix removal by forming endocytotic vesicles, and the potential function of these vesicles in either removing hydrolyzed amelogenins, or transporting proteinases to the maturation stage enamel matrix will be investigated. The long-term goal of this proposal is to determine the function of WDR72 in tooth organ development. These studies will also shed light on the role of WDR72 in other organ systems. To test the hypothesis that WDR72 is involved in vesicle trafficking, we will focus on the following 2 specific aims: 1) To determine whether WDR72 mediates vesicle trafficking in ameloblasts; 2) To determine the effects of WDR72 on enamel matrix protein deposition, processing and reabsorption These findings in these studies will direct our understanding of the role of WDR72 on enamel matrix removal, vesicle trafficking and enamel mineralization, We anticipate that these studies will lead to a larger R01 proposal on the role of WDR72 in teeth, and translational studies related to amelogenesis imperfecta. .